New drug targets are urgently needed for the development of primary and adjuvant therapies for pancreatic ductal adenocarcinoma. Nearly all pancreatic ductal adenocarcinomas are caused by activating mutations in the Kras gene. Pharmacological inhibition of Kras has been unsuccessful. However, oncogenic Kras activates several enzymes that are more easily targeted with small molecule inhibitors that can be developed as drugs. Our proposed study focuses on one such enzyme, namely phosphatidylinositol 3-kinase (PI3K) p110. Our preliminary studies showed that ablation of the p110 gene in the mouse pancreas completely prevented the development of pancreatic cancer caused by oncogenic Kras without causing any detectable harmful effects. These results suggest the exciting possibility that p110 might be a legitimate drug target for the treatment of pancreatic cancer. This proposal will extend upon these results through the use of novel inducible mouse models that have high translational relevance for the development of pancreatic cancer treatment. First, the dependence of already-formed tumors on p110 will be investigated using genetically engineered mice whose p110 expression can be modulated at will. This scenario will closely model the clinical situation where pancreatic cancer patients are treated with PI3K inhibitors. Second, the necessity of catalytic activity of p110 in pancreatic oncogenesis will be determined using mice expressing a kinase-dead form of p110, and the sufficiency of catalytic activity will be tested using mice expressing a constitutively active formof the kinase. Since these mouse models are also inducible, their requirement for tumor maintenance will also be investigated as a secondary study. Finally, the importance of the physical interaction between Ras and p110 will be investigated using knock-in mice expressing a mutant p110 that is incapable of binding to Ras. Results from these studies will not only validate the legitimacy of p110 as a suitable drug target for pancreatic cancer, but also elucidate the mechanistic role of p110 in pancreatic oncognesis so as to provide a better understanding of this therapeutic target. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a deadly disease that is highly resistant to existing therapies, and there is an urgent need for new drug targets to be developed. The goal of this proposal is to validate a potential new drug target, the enzyme phosphatidylinositol 3-kinase p110, for pancreatic cancer through the use of novel mouse models that resemble the clinical situation of pancreatic cancer patients. Positive results from this study will strongl suggest that p110 inhibition will be effective in the treatment of pancreatic cancer patients and warrant further clinical studies.